Clinical relevance of biochemical modulation of 5-fluorouracil

Biochemical modulation is a special type of combination chemotherapy which aims to selectively improve the therapeutic index by increasing the antitumor effect and protecting against toxic side effects. Biochemical modulation seems to be an attractive way to circumvent quantitative and qualitative heterogeneity of tumors. In the past decade a number of biochemical modulation approaches have been tested to improve the activity of 5-fluorouracil (5FU). 5FU itself has only modest anticancer activity but has been shown to be a very attractive target for biochemical modulation. A number of the combinations have been ineffective in the clinic despite extensive testing in a number of schedules. Some other combinations were initially tested in an inappropriate schedule, but were active when applied in another schedule. The latter was made possible by a systematic preclinical development of combinations with a proper translation to the clinic accompanied by pharmacodynamic evaluation. This review describes a number of biochemical modulation combinations, both inactive and active. The main conclusion is that properly applied biochemical modulation schedules may lead to successful use in the clinic.